OFQ, a heptadeca peptide, has been isolated from rat brain and is a natural ligand to a G-protein coupled receptor (OFQ-R), found at high levels in brain tissue. OFQ exhibits agonistic activity at the OFQ-R both in vitro and in vivo.
Julius (Nature 377,476, [1995]) discusses the discovery of OFQ noting that this peptide shares greatest sequence homology with dynorphin A, an established endogenous ligand for opioid receptors. OFQ inhibits adenylate cyclase in CHO(LC 132.sup.+) cells in culture and induces hyperalgesia when administered intra-cerebroventricularly to mice. The pattern of results indicate that this heptadecapeptide is an endogenous agonist of the LC 132 receptor and it appears to have pro-nociceptive properties. It has been described that when injected intra-cerebroventricularly in mice, OFQ slowes down locomotive activity and induces hyperalgesia and it has been concluded that OFQ may act as a brain neurotransmitter to modulate nociceptive and locomotive behavior.
In the following references these indications have been described:
Nociceptin/orphanin FQ and the opioid receptor-like ORL1 receptor, Eur. J. Pharmacol., 340: 1-15, 1997; PA1 The orphan opioid receptor and its endogenous ligand nociceptin/orphanin FQ, Trends Pharmacol. Sci., 18:293-300, 1997; PA1 Orphanin FQ is a functional anti-opioid peptide, Neuroscience, 75:333-337, 1996; PA1 Orphanin FQ/nociceptin-lack of antinociceptive, hyperalgesic or allodynic effects in acute thermal or mechanical tests, following intracerebroventricular or intrathecal administration to mice or rats, Eur. J. pain, 2: 267-280, 1998; PA1 Orphanin FQ acts as an anxiolytic to attenuate behavioral responses to stress, Proc. Natl. Acad. Sci., USA, 94: 14854-14858, 1997; PA1 Orphanin FQ, an agonist of orphan opioid receptor ORL1, stimulates feeding in rats, Neuroreport, 8: 369-371, 1996; PA1 Facilitation of long-term potentiation and memory in mice lacking nociceptin receptors, Nature, 394: 577-581, 1998; PA1 Distribution of nociceptin/orphanin FQ receptor transcript in human central nervous system and immune cells, J. Neuroimmuno, 81: 184-192, 1998. PA1 R.sup.2, R.sup.3 are hydrogen; hydroxy; lower alkyl; .dbd.O; or phenyl, optionally substituted by lower alkyl, halogen or alkoxy; PA1 R.sup.4 is hydrogen; lower akyl; --(CH.sub.2).sub.n CH(OH)CF.sub.3 ; --(CH.sub.2).sub.n C.sub.3-6 -cycloalkyl; phenyl; benzyl; tetrahydrofuran-3-yl; --(CH.sub.2).sub.n OCH.sub.2 C.sub.6 H.sub.5 ; --(CH.sub.2).sub.n morpholinyl; 3-methyl-oxetan-3-yl-methyl; --(CH.sub.2).sub.n CH.sub.2 OH; --S(O).sub.2 -lower alkyl; --C(O)-lower alkyl; --C(O)CF.sub.3 ; --C(O)(CH.sub.2).sub.n OCH.sub.3 ; --(CH.sub.2).sub.n C(O)N(lower alkyl).sub.2 ; --S(O).sub.2 heteroaryl; --C(O)heteroaryl; --S(O).sub.2 -phenyl; --S(O).sub.2 --N(lower alkyl).sub.2 ; --C(O)-C.sub.3-6 -cycloalkyl; --C(O)O-phenyl; or --C(O)O-lower alkyl: PA1 R.sup.5 is hydrogen; halogen; lower alkyl; trifluoromethyl or lower alkoxy; PA1 n is 0-3; PA1 a) reductively aminating a compound of formula ##STR2## with a compound of formula ##STR3## wherein R.sup.1 -R.sup.5 have the significances given above, or PA1 b) reducing a compound of formula ##STR4## to a compound of one of the formulae ##STR5## wherein R.sup.1, R.sup.4 and R.sup.5 have the significances given above, or PA1 c) acylating or sulfonylating a compound of formula ##STR6## to a compound of formula ##STR7## wherein R.sup.1 -R.sup.3 and R.sup.5 have the significances given above and Q is --S(O).sub.2 -lower alkyl; --C(O)-lower alkyl; --C(O)CF.sub.3 ; --C(O)(CH.sub.2).sub.n OCH.sub.3 ; --C(O)N(lower alkyl).sub.2 ; --S(O).sub.2 -heteroaryl; --C(O)-heteroaryl; --S(O).sub.2 -phenyl; --C(O)-C.sub.3-6 -cycloalkyl; or --C(O)O-lower alkyl and n is 0-3, PA1 or PA1 d) debenzylating a compound of formula ##STR8## to a compound of formula ##STR9## wherein R.sup.1 -R.sup.3 and R.sup.5 have the significances given above, except that R.sup.2 and R.sup.3 are not .dbd.O or hydoxy, PA1 e) reacting a ketone of formula ##STR10## with N-phenyl-glycine of formula ##STR11## and trapping the forming azomethine-ylides of formula ##STR12## in a compound of formula ##STR13## wherein the substituents have the significances given above, or, if desired, PA1 converting a racemic mixture into its enantiomeric components thus obtaining optically pure compounds, and PA1 converting a compound of formula I obtained into a pharmaceutically acceptable acid addition salt.
The compounds of the present invention intereact with the OFQ receptor and objects of the present invention are the compounds of formula I and pharmaceutically acceptable addition salts thereof, racemic mixtures and their corresponding enantiomers, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture as well as the use of the above-mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred above, or in the manufacture of corresponding medicaments.